N-Acetylphytosphingosine Enhances the Radiosensitivity of Tumor Cells by Increasing Apoptosis

2005 ◽  
Vol 277-279 ◽  
pp. 536-541
Author(s):  
Young Soo Han ◽  
Yun Hwa Kim ◽  
Yeon Sook Yun ◽  
Soo Jin Jeon ◽  
Ki Sung Kim ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mammalian Cells ◽  
Second Messengers ◽  
Clonogenic Survival ◽  
Jurkat Cells ◽  
Human Leukemia ◽  
Apoptotic Effect ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
Exogenous Treatment

Ceramides are well-known second messengers which mediate apoptosis, proliferation, differentiation in mammalian cells, but the physiological roles of phytosphingosines are poorly understood. We hypothesized that one of the phytosphingosine derivatives, N-acetylphytosphingosine (NAPS) can induce apoptosis in human leukemia Jurkat cell line and increase apoptosis in irradiated MDA-MB-231 cells. We first examined the effect of NAPS on apoptosis of Jurkat cells. NAPS had a more rapid and stronger apoptotic effect than C2-ceramide in Jurkat cells and significant increase of apoptosis was observed at 3 h after treatment. In contrast, the apoptosis induced by C2-ceramide was observed only after 16 h of treatment. NAPS induced apoptosis was mediated by caspase 3 and 8 activation and inhibited by z-VAD-fmk. Ceramide plays a pivotal role in radiation induced apoptosis. We postulated that exogenous treatment of NAPS sensitizes tumor cells to ionizing radiation, since NAPS might be used as a more effective alternative to C2-ceramide. As expected, NAPS decreased clonogenic survival of irradiated MDA-MB-231 cells dose dependently, and apoptosis of irradiated cells in the presence of NAPS was increased through the caspase activation. Taken together, NAPS is an effective apoptosis-inducing agent, which can be readily synthesized from yeast sources, and is a potent alternative to ceramide for the further study of ceramide associated signaling and the development of radiosensitizing agent.

Wild-type, mitochondrial and ER-restricted Bcl-2 inhibit DNA damage-induced apoptosis but do not affect death receptor-induced apoptosis

2001 ◽  
Vol 114 (23) ◽  
pp. 4161-4172
Author(s):  
Justine Rudner ◽  
Albrecht Lepple-Wienhues ◽  
Wilfried Budach ◽  
Johannes Berschauer ◽  
Björn Friedrich ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Transmembrane Domain ◽  
Cytochrome B5 ◽  
Death Receptor ◽  
Jurkat Cells ◽  
Wild Type ◽  
Specific Sequence ◽  
Apoptotic Effect ◽  
Radiation Induced ◽  
Induced Apoptosis

The proto-oncogene Bcl-2 is expressed in membranes of mitochondria and endoplasmic reticulum and mediates resistance against a broad range of apoptotic stimuli. Although several mechanisms of Bcl-2 action have been proposed, its role in different cellular organelles remains elusive. Here, we analyzed the function of Bcl-2 targeted specifically to certain subcellular compartments in Jurkat cells. Bcl-2 expression was restricted to the outer mitochondrial membrane by replacing its membrane anchor with the mitochondrial insertion sequence of ActA (Bcl-2/MT) or the ER-specific sequence of cytochrome b5 (Bcl-2/ER). Additionally, cells expressing wild-type Bcl-2 (Bcl-2/WT) or a transmembrane domain-lacking mutant (Bcl-2/ΔTM) were employed. Apoptosis induced by ionizing radiation or by the death receptors for CD95L or TRAIL was analyzed by determination of the mitochondrial membrane potential (ΔΨm) and activation of different caspases. Bcl-2/WT and Bcl-2/MT strongly inhibited radiation-induced apoptosis and caspase activation, whereas Bcl-2/ΔTM had completely lost its anti-apoptotic effect. Interestingly, Bcl-2/ER conferred protection against radiation-induced mitochondrial damage and apoptosis similarly to Bcl-2/MT. The finding that ER-targeted Bcl-2 interfered with mitochondrial ΔΨm breakdown and caspase-9 activation indicates the presence of a crosstalk between both organelles in radiation-induced apoptosis. By contrast, Bcl-2 in either subcellular position did not influence CD95- or TRAIL-mediated apoptosis.

Abundance of cyclin B1 regulates γ-radiation–induced apoptosis

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2645-2650 ◽  
Author(s):  
Lisa A. Porter ◽  
Gurmit Singh ◽  
Jonathan M. Lee
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Mammalian Cells ◽  
Hematopoietic Cells ◽  
Cyclin B1 ◽  
Regulatory Subunit ◽  
Potent Inducer ◽  
Γ Radiation ◽  
Radiation Induced ◽  
Induced Apoptosis

Abstract γ-Radiation is a potent inducer of apoptosis. There are multiple pathways regulating DNA damage-induced apoptosis, and we set out to identify novel mechanisms regulating γ-radiation–induced apoptosis in hematopoietic cells. In this report, we present data implicating the cyclin B1 protein as a regulator of apoptotic fate following DNA damage. Cyclin B1 is the regulatory subunit of the cdc2 serine/threonine kinase, and accumulation of cyclin B1 in late G2 phase of the cell cycle is a prerequisite for mitotic initiation in mammalian cells. We find that abundance of the cyclin B1 protein rapidly increases in several mouse and human hematopoietic cells (Ramos, DP16, HL60, thymocytes) undergoing γ-radiation–induced apoptosis. Cyclin B1 accumulation occurs in all phases of the cell cycle. Antisense inhibition of cyclin B1 accumulation decreases apoptosis, and ectopic cyclin B1 expression is sufficient to induce apoptosis. These observations are consistent with the idea that cyclin B1 is both necessary and sufficient for γ-radiation-induced apoptosis.

Nitric Oxide–Induced Apoptosis in Human Leukemic Lines Requires Mitochondrial Lipid Degradation and Cytochrome C Release

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2342-2352 ◽  
Author(s):  
Alexey Ushmorov ◽  
Frank Ratter ◽  
Volker Lehmann ◽  
Wulf Dröge ◽  
Volker Schirrmacher ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cytochrome C ◽  
Mitochondrial Protein ◽  
Jurkat Cells ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Cytochrome C Release ◽  
Mitochondrial Functions ◽  
Mitochondrial Lipid ◽  
Induced Apoptosis

Abstract We have previously shown that nitric oxide (NO) stimulates apoptosis in different human neoplastic lymphoid cell lines through activation of caspases not only via CD95/CD95L interaction, but also independently of such death receptors. Here we investigated mitochondria-dependent mechanisms of NO-induced apoptosis in Jurkat leukemic cells. NO donor glycerol trinitrate (at the concentration, which induces apoptotic cell death) caused (1) a significant decrease in the concentration of cardiolipin, a major mitochondrial lipid; (2) a downregulation in respiratory chain complex activities; (3) a release of the mitochondrial protein cytochrome c into the cytosol; and (4) an activation of caspase-9 and caspase-3. These changes were accompanied by an increase in the number of cells with low mitochondrial transmembrane potential and with a high level of reactive oxygen species production. Higher resistance of the CD95-resistant Jurkat subclone (APO-R) cells to NO-mediated apoptosis correlated with the absence of cytochrome c release and with less alterations in other mitochondrial parameters. An inhibitor of lipid peroxidation, trolox, significantly suppressed NO-mediated apoptosis in APO-S Jurkat cells, whereas bongkrekic acid (BA), which blocks mitochondrial permeability transition, provided only a moderate antiapoptotic effect. Transfection of Jurkat cells with bcl-2 led to a complete block of apoptosis due to the prevention of changes in mitochondrial functions. We suggest that the mitochondrial damage (in particular, cardiolipin degradation and cytochrome c release) induced by NO in human leukemia cells plays a crucial role in the subsequent activation of caspase and apoptosis.

scholarly journals 5-Aminoimidazole-4-carboxamide riboside induces apoptosis in Jurkat cells, but the AMP-activated protein kinase is not involved

2003 ◽  
Vol 370 (3) ◽  
pp. 1027-1032 ◽  
Author(s):  
José M. LÓPEZ ◽  
Antonio F. SANTIDRIÁN ◽  
Clara CAMPÀS ◽  
Joan GIL
Keyword(s):  
Protein Kinase ◽  
Cell Types ◽  
Jurkat Cells ◽  
Nucleoside Transport ◽  
Cytochrome C Release ◽  
Nucleotide Biosynthesis ◽  
Apoptotic Effect ◽  
Nucleoside Transport Inhibitor ◽  
Induced Apoptosis ◽  
Amp Activated Protein Kinase

5-Aminoimidazole-4-carboxamide (AICA) riboside, a precursor of purine nucleotide biosynthesis, induces apoptosis in Jurkat cells. Incorporation of AICAriboside into the cells is necessary for this effect since addition of nitrobenzylthioinosine, a nucleoside-transport inhibitor, completely protects Jurkat cells from apoptosis. Adenosine, but not other nucleosides, also protects Jurkat cells from AICAriboside-induced apoptosis. The apoptotic effect is caspase-dependent since caspases 9 and 3 are activated and the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD.fmk) blocks apoptosis. Furthermore, AICAriboside induces mitochondrial cytochrome c release. AICAriboside, when phosphorylated to AICAribotide (ZMP), is a specific activator of the AMP-activated protein kinase (AMPK) in certain cell types. However, AICAriboside does not activate AMPK in Jurkat cells. Moreover, 5-iodotubercidin, an inhibitor of AICAriboside phosphorylation, does not inhibit apoptosis in Jurkat cells. These results indicate that AICAriboside induces apoptosis independently of ZMP synthesis and AMPK activation in Jurkat cells.

scholarly journals Low-dose radiation-induced apoptosis in human leukemia K562 cells through mitochondrial pathways

2014 ◽  
Vol 10 (3) ◽  
pp. 1569-1575 ◽  
Author(s):  
YONG XIN ◽  
HAI-BIN ZHANG ◽  
TIAN-YOU TANG ◽  
GUI-HONG LIU ◽  
JIAN-SHE WANG ◽  
...  
Keyword(s):  
Low Dose ◽  
K562 Cells ◽  
Human Leukemia ◽  
Low Dose Radiation ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
Dose Radiation ◽  
Human Leukemia K562 Cells

scholarly journals Effects of Ceramide Inhibition on Radiation-induced Apoptosis in Human Leukemia MOLT-4 Cells

2006 ◽  
Vol 47 (1) ◽  
pp. 19-25 ◽  
Author(s):  
Eriko TAKAHASHI ◽  
Osamu INANAMI ◽  
Taketoshi ASANUMA ◽  
Mikinori KUWABARA
Keyword(s):  
Human Leukemia ◽  
Radiation Induced ◽  
Induced Apoptosis

Protein changes associated with ionizing radiation-induced apoptosis in human prostate epithelial tumor cells

2007 ◽  
pp. 485-494
Author(s):  
Sarada C. Prasad ◽  
Viatcheslav A. Soldatenkov ◽  
Michael R. Kuettel ◽  
Peter J. Thraves ◽  
Xiaojun Zou ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Tumor Cells ◽  
Human Prostate ◽  
Epithelial Tumor ◽  
Radiation Induced ◽  
Epithelial Tumor Cells ◽  
Induced Apoptosis

Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD

2012 ◽  
Vol 302 (6) ◽  
pp. E615-E625 ◽  
Author(s):  
Yuria Saito ◽  
Yuko Tanaka ◽  
Yuichi Aita ◽  
Kiyo-aki Ishii ◽  
Tatsuhiko Ikeda ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pc12 Cells ◽  
Kinase Inhibitor ◽  
Active Agent ◽  
Dependent Manner ◽  
Human Neuroblastoma ◽  
Downstream Effectors ◽  
Apoptotic Effect ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that mainly targets vascular endothelial growth factor receptors (VEGFRs). Very recently, sunitinib has been shown to be an active agent for the treatment of malignant pheochromocytomas. However, it is unclear whether sunitinib acts only through an antiangiogenic mechanism or whether it may also directly target tumor cells. Sunitinib markedly induced apoptosis of PC12 cells in a dose-dependent and time-dependent manner. Furthermore, in support of these findings, we found that sunitinib induced a reduction in the expression of the antiapoptotic molecule Bcl-2 as well as dephosphorylation of the proapoptotic molecule BAD, which results in the activation of BAD in these cells. Consistent with these apoptotic effects, our results showed that sunitinib inhibited phosphorylation of Akt and mTOR and was followed by a reduction of S6K1, which is a well-known target of mTOR. Knockdown of VEGFR-2 attenuated the sunitinib-induced effects, including apoptosis and inhibition of signaling pathways such as the phosphorylation of Akt as well as mTOR, and Bcl-2, which confirmed that these effects could be mediated by VEGFR-2. In addition, silencing of S6K1 induced apoptosis accompanied by a decrease in the phosphorylation of BAD and Bcl-2, similar to that observed with sunitinib treatment. Thus, these results together suggest that sunitinib initially exerts its apoptotic effect through the inhibition of VEGFR-2, which, when followed by reduction of its downstream effectors, including Akt/mTOR/S6K1, may lead to inhibition of the antiapoptotic molecule Bcl-2 and activation of the proapoptotic molecule BAD in PC12 cells. However, PC12 cells do not precisely reflect the pathogenesis of malignant cells. Therefore, we confirmed the key findings by replicating these experiments in human neuroblastoma SK-N-SH cells.

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